ABSTRACT

Context Many patients with chronic angina experience anginal episodes despite
revascularization and antianginal medications. In a previous trial, antianginal
monotherapy with ranolazine, a drug believed to partially inhibit fatty acid
oxidation, increased treadmill exercise performance; however, its long-term
efficacy and safety have not been studied in combination with β-blockers
or calcium antagonists in a large patient population with severe chronic angina.

Objectives To determine whether, at trough levels, ranolazine improves the total
exercise time of patients who have symptoms of chronic angina and who experience
angina and ischemia at low workloads despite taking standard doses of atenolol,
amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic
evidence of myocardial ischemia, effect on angina attacks and nitroglycerin
use, and effect on long-term survival in an open-label observational study
extension.

Design, Setting, and Patients A randomized, 3-group parallel, double-blind, placebo-controlled trial
of 823 eligible adults with symptomatic chronic angina who were randomly assigned
to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the
118 participating ambulatory outpatient settings in several countries were
enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA)
trial from July 1999 to August 2001 and followed up through October 31, 2002.

Main Outcome Measures Change in exercise duration, time to onset of angina, time to onset
of ischemia, nitroglycerin use, and number of angina attacks.

Results Trough exercise duration increased by 115.6 seconds from baseline in
both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P = .01). The times to angina and to electrocardiographic
ischemia also increased in the ranolazine groups, at peak more than at trough.
The increases did not depend on changes in blood pressure, heart rate, or
background antianginal therapy and persisted throughout 12 weeks. Ranolazine
reduced angina attacks and nitroglycerin use by about 1 per week vs placebo
(P<.02). Survival of 750 patients taking ranolazine
during the CARISA trial or its associated long-term open-label study was 98.4%
in the first year and 95.9% in the second year.

Figures in this Article

Chronic angina is a debilitating illness affecting at least 6.6 million
US residents.1 Patients report limitation of
their work and other activities 2 to 3 times more frequently than what is
reported by the general population.2 Despite
the continued explosive growth in myocardial revascularization,1 largely
to prevent angina attacks,3 most patients continue
to require antianginal drugs; furthermore, despite both revascularization
and pharmacotherapy, up to 26% of patients still experience attacks.4,5

Currently available antianginal drugs (β-blockers, calcium channel
blockers, and nitrates) all work to reduce myocardial oxygen demand by decreasing
1 or more indices of cardiac work (although the latter 2 classes may also
improve oxygen supply). However, for many patients receiving treatment, angina
persists, illustrating the need for a drug with an anti-ischemic mechanism
complementary and therefore potentially additive to those of the existing
agents.

The antianginal action of ranolazine may be related to partial inhibition
of fatty acid oxidation,6,7 which
can produce anti-ischemic effects without depressing hemodynamic function.8 Inhibition of fatty acid oxidation reciprocally increases
glucose oxidation, which generates more adenosine triphosphate for each molecule
of oxygen consumed.9 This shift in substrate
selection may reduce myocardial oxygen supply needed to support a given level
of cardiac work so that for any level of coronary flow, ischemia should be
less likely.

The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial
was the first placebo-controlled trial to establish the antianginal and anti-ischemic
effects of ranolazine monotherapy, demonstrating increased exercise tolerance
and prolonged times to exercise-induced angina and ischemic ST-segment depression
with twice-daily ranolazine doses ranging from 500 mg to 1500 mg.10 The Combination Assessment of Ranolazine In Stable
Angina (CARISA) trial assessed the antianginal and anti-ischemic effects of
ranolazine in symptomatic chronic angina patients with severe coronary disease,
evidenced by exercise-induced myocardial ischemia at low workloads despite
treatment with standard doses of atenolol, amlodipine, or diltiazem.

METHODS

Study Overview

CARISA was a double-blind, 3-group parallel trial in which patients
were randomly assigned to receive twice-daily placebo or 750 mg or 1000 mg
of sustained-release ranolazine for 12 weeks (CV Therapeutics, Palo Alto,
Calif) (Figure 1). Patients were
stratified according to the antianginal therapy they were taking at the time
of enrollment (50 mg of atenolol , 180 mg of diltiazem in a once-a-day formulation,
or 5 mg of amlodipine once a day). The choice of back-ground therapy was at
the discretion of the investigator and the doses were fixed throughout the
study. One patient interrupted background therapy (atenolol) for 1 day prior
to performing the week 12 exercise treadmill test. The protocol was approved
by the appropriate institutional review board governing each participating
center, and all participants signed a written informed consent form that explained
the risks and benefits of study participation.

Figure 1. Patient Study Flow Diagram

Safety data are presented for all 823 patients who received at least
1 dose of study medication. Efficacy data are available from 791 patients
(737 patients completed the full 12-week protocol and 54 patients had the
last observation carried forward).

The primary aim of the study was to compare the effects of ranolazine
vs placebo on treadmill exercise duration at trough ranolazine levels (ie,
12 hours after dosing). Secondary efficacy end points included exercise duration
at the approximate time of peak drug levels (ie, 4 hours after dosing), times
to angina and to 1 mm ST-segment depression at peak and trough, and the angina
attacks and sublingual nitroglycerin uses reported in the patients' daily
diaries. Vital signs were measured and recorded, and drug tolerability and
safety were assessed.

Patient Selection

All patients had coronary artery disease (confirmed by angiography,
documented prior myocardial infarction, or a diagnostic stress myocardial
imaging study) and a minimum 3-month history of exertional angina. Patients
were withdrawn from antianginal drugs (other than the required background
therapy) for at least 5 days before the first qualifying exercise test and
for the remainder of the trial. At the screening visit, which was at the start
of the washout phase, a medical history, physical examination, resting electrocardiogram
(ECG), blood pressure and heart rate measurements, and clinical laboratory
tests were performed. Eligible patients had reproducible angina, ischemic
ST-segment depression of at least 1 mm and limited exercise capacity on treadmill
testing (3-9 minutes on a modified Bruce protocol) while receiving required
background antianginal treatment with the most commonly used agents and doses
in clinical practice (atenolol 50 mg, amlodipine 5 mg, or diltiazem 180 mg
once daily). Factors that precluded satisfactory interpretation of the ECG
(eg, resting ST-segment depression ≥1 mm in any lead, left bundle-branch
block, digoxin therapy), class III or IV heart failure, or an acute coronary
syndrome or coronary revascularization procedure within the prior 2 months
were exclusion criteria. Voltage criteria for left ventricular hypertrophy
in the absence of repolarization abnormalities were not an exclusion criterion.

Randomization

Quintiles (UK) Limited (Bracknell, England) generated separate randomization
schedules using a random number generator in SAS version 6.12 (SAS Institute,
Cary, NC). Randomization was stratified by the 3 background antianginal therapies
(atenolol, amlodipine, and diltiazem), using a block size of 6. The schedules
were sent to Brecon Pharmaceuticals Ltd (Hay-on-Wye, England), for drug packaging
and preparation of the code break envelopes. A second paper copy and a disk-based
electronic backup were filed securely in a sealed envelope at Quintiles Limited.
Brecon provided the sealed medication assignment envelope to the clinical
units for each patient randomized in the study. Depending on expected enrollment,
each site received study medication in either single or multiple sets of mini
blocks. The medication assignment was provided to the principal investigator
in a sealed envelope to be used only if knowledge of the therapeutic assignment
was required to treat a medical emergency.

Exercise Protocol

Eligible patients entered a single-blind, placebo-treatment qualifying
phase during which they had 2 modified Bruce exercise treadmill tests11 conducted 1 week apart. A supine standard 12-lead
ECG was obtained before each exercise treadmill test, and standing torso ECGs
were monitored throughout the exercise testing. A core ECG laboratory (St
Louis University; St Louis, Mo) blinded to treatment assignment interpreted
all rest and exercise ECGs. All rest ECGs were classified using the Minnesota
code. All exercise ECGs were analyzed using customized software as previously
described.12 The longest QT interval in each
12-lead ECG was reported, corrected using Bazett's formula. QT dispersion
measurements, defined as the difference in milliseconds between the longest
and shortest QT interval observed in the ECG tracing, were recorded.

Exercise-induced ECG ischemia was defined as the new development of
horizontal or down-sloping ST-segment depression (≥1 mm at 80 milliseconds
after the J point) vs baseline tracing. For patients with permitted baseline
ST-depression at rest (<1 mm), qualifying ST-segment depression was defined
as additional ST depression of at least 1 mm below the resting value. Patients
were randomized into the double-blind phase of the study if they developed
exercise-limiting angina and ECG ischemia between 3 and 9 minutes during both
qualifying exercise treadmill tests, and the difference in exercise duration
between the 2 tests did not exceed 20% of the longer test or 1 minute. Subsequent
exercise tests were performed at trough drug levels 2, 6, and 12 weeks after
randomization. At 2 and 12 weeks after randomization, a peak exercise test
was performed approximately 4 hours after dosing, and on the same day, after
the 12-hour postdosing trough exercise test had been completed.

Statistical Analyses

Under the assumptions of normally distributed data and an SD of 80 seconds,
a sample size of 462 evaluable patients was projected to have 90% power to
detect a difference of 30 seconds in the primary end point (exercise duration
at trough) between 750 mg of ranolazine and placebo and between 1000 mg of
ranolazine and placebo. After considering a potential 20% dropout rate, it
was estimated that 577 patients would need to be enrolled. To reassess the
sample size estimate, the protocol specified that a treatment-blinded interim
assessment of the SD about the primary end point (change from baseline in
total exercise treadmill test duration at trough) would be performed when
231 or one half of the planned completed study patients had been randomized
and followed up for 12 weeks. The recalculation of sample size, using only
blinded data, was adjusted based on the estimated SD of the primary efficacy
parameter (exercise duration at trough) from the aggregate data and yielded
a revised SD estimate that increased the sample size to at least 810 patients
(adjusted for dropouts).13- 15

The primary efficacy parameter was the change from baseline in exercise
treadmill time at trough, analyzed using an analysis of variance model with
terms for treatment, pooled site, background therapy, and baseline exercise
treadmill time, using the last observation carried forward after randomization
on an intent-to-treat basis. For the primary efficacy parameter, a 2-stage,
step-down procedure, based on closed testing and union intersection principles,
maintained the experiment-wise type I error rate at .05.16,17 The
first step compared the 2 ranolazine treatment doses with placebo. When statistical
significance was achieved, the individual doses were compared with placebo.
All comparisons were carried out using 2-sided α of .05.

Angina frequency and nitroglycerin consumption per week of double-blind
treatment were descriptively summarized. Because the data were not normally
distributed, treatment comparisons between ranolazine and placebo were obtained
from a nonparametric analysis of variance model using ranked data with effects
of treatment, baseline covariate, pooled site, and background therapy.18A survival curve was prepared using Kaplan-Meier estimates
for 750 patients, including 554 who received ranolazine in the CARISA trial
and 196 patients who began open-label ranolazine after receiving double-blind
placebo during the CARISA trial. Patients were censored 1 day after their
last treatment with ranolazine. Data are given as least square means (SE unless
otherwise noted).

RESULTS

The CARISA trial began in July 1999 and ended in August 2001. Long-term
follow-up is reported through October 31, 2002. Patients (n = 823) were randomized
at 118 investigational sites in 15 countries, received at least 1 dose of
the double-blind study medication, and contributed safety data. At enrollment,
354 patients (43%) were taking atenolol; 256 (31.1%), amlodipine; and 213
(25.9%), diltiazem. Baseline characteristics, including the distribution of
the background antianginal drugs, angina frequency, and nitroglycerin use,
were similar across the 3 treatment groups at baseline, although marginally
fewer patients in the placebo group had undergone bypass surgery (Table 1). Two hundred sixty-nine patients
were assigned to receive placebo, and 279 were assigned to receive 750 mg,
and 275 to receive 1000 mg of ranolazine (Figure 1). Each medication dosage was prescribed to be taken twice
a day.

Treadmill Exercise Testing

The primary end point of the study was met. Exercise duration for those
taking either ranolazine dose (pooled) was increased compared with placebo
(P = .01). Each individual ranolazine dose increased
treadmill exercise duration at both trough (P = .03)
and peak (P<.02) (Table 2). This effect was sustained throughout 12 weeks of therapy
at both dosage levels (Figure 2).
Similar results were observed for times to angina and to ECG ischemia. Effects
at peak were generally greater than at trough. Antianginal background therapy
did not significantly modify the response to ranolazine (Figure 3).

In addition to testing differences between placebo and ranolazine using
last observation carried forward analysis, a sensitivity analysis of the primary
efficacy variable was found to support the conclusions obtained. We found
that the study would have failed to demonstrate efficacy if the 11 patients
with missing data in the placebo group had an increase from baseline in exercise
duration of 91.7 seconds while the 21 patients taking ranolazine with missing
data had a decrease from baseline of 40 seconds or more, which is unlikely.
Finally, differences between treatment groups were tested in all patients
after 12 weeks of treatment. The results were not appreciably different from
results obtained using the last observation carried forward method.

Angina Frequency and Nitroglycerin Consumption

At baseline, patients were very symptomatic, experiencing an average
of 4.5 angina attacks per week, prompting nearly as many nitroglycerin uses.
Ranolazine reduced the mean (SE) angina attacks per week from 3.3 (0.3) for
placebo to 2.5 (0.2) for 750 mg (P = .006) to 2.1
(0.2) for 1000 mg (P<.001) ranolazine. Ranolazine
also significantly reduced nitroglycerin consumption with a similar dose response
(Figure 4).

Figure 4. Angina Frequency and Nitroglycerin
Consumption in the Intent-to-Treat Population

Adverse Events

Adverse events were reported in 26.4% of patients in the placebo group
and 31.2% in the 750-mg and 32.7% in the 1000-mg ranolazine groups. The most
common dose-related adverse effects were constipation, dizziness, nausea,
and asthenia (≤7.3% in both ranolazine groups; ≥0.7% in the placebo
group). Mortality during the 12-week randomization trial (including the 14-day
safety follow-up) in the placebo group was 1.1% (3/269) and was 0.7% (2/279)
in the 750-mg and 0.4% (1/275) in the 1000-mg ranolazine groups. Five patients
in the 1000-mg ranolazine group reported experiencing syncope. None were injured
during their events; all recovered spontaneously, and no symptoms, signs,
or ECG evidence of ventricular tachyarrhythmias were recorded.

ECG Findings

Small, dose-related increases in Bazett's QTc interval occurred with
ranolazine vs placebo. At week 12, the mean (SE) QTc were 421.5 (1.0) milliseconds
for the placebo group and 427.6 (1.0) milliseconds for the 750-mg and 430.7
(1.0) miliseconds for the 1000-mg ranolazine groups. The mean (SE) increases
over placebo were 6.1 (1.3) milliseconds for the 750-mg and 9.2 (1.4) milliseconds
for the 1000-mg ranolazine groups (P <.001). Ranolazine
did not affect QT dispersion. No torsade de pointes was observed.

Long-term Follow-up

As of October 31, 2002, among 750 patients who took ranolazine during
the CARISA trial or during the open-label follow-up study, 685 had received
their first dose at least 1 year earlier; 292 patients received their first
dose at least 2 years earlier. Of these, 480 (70.1%) after year 1 and 173
(59.2%) after year 2 continued taking ranolazine. After 2 years, 128 (74.0%)
of 173 patients were still receiving doses of less than 1000 mg of ranolazine
twice a day. Survival rates for those taking ranolazine were 98.4% (95% CI,
97.4%-99.5%) at year 1 and 95.9% (95% CI, 94.0%-97.7%) at year 2 .

COMMENT

The frequency of angina attacks is the most significant determinant
of quality of life for patients with chronic angina, even after adjusting
for their many comorbidities.19 Consequently,
an increasing majority of revascularization procedures are done for angina
relief rather than for improving survival, especially in the United States.1,3 Nevertheless, a year after their procedures,
most patients still require antianginal medications and up to 26% of them
still have angina attacks.4,5

We report the first evidence that ranolazine can reduce both angina
frequency and nitroglycerin consumption when added to a standard dose of 1
of 3 frequently prescribed antianginal drugs: atenolol, amlodipine or diltiazem.
The decrease in angina attacks vs placebo was slightly less than 1 per week
for those in the 750-mg and somewhat more than 1 per week for those in the
1000-mg ranolazine groups(Figure 4).
Exercise duration after 12 weeks of ranolazine therapy increased by 115.6
seconds at trough for those taking ranolazine compared with 91.7 seconds for
those taking placebo. This net increase is similar to that observed with ranolazine
as monotherapy in an earlier placebo-controlled randomized trial10 and
to improvements observed in some trials of current therapies added to one
another.20,21 Of note, however,
in several earlier studies, current antianginal drugs in combination have
not always improved exercise capacity compared with monotherapy.22- 24 Exercise
testing also confirmed continuous antianginal and anti-ischemic effects throughout
the 12-hour dosing interval, maintained from 2 through 12 weeks of treatment.
The absence of an evident dose response in exercise parameters between 750-mg
and 1000-mg ranolazine groups in the CARISA trial contrasts to the dose effects
observed for angina frequency and nitroglycerin use in this study. In the
MARISA trial,10 a broader dose range (500-1500
mg of ranolazine twice daily) likely facilitated the demonstration of a clear
dose effect on exercise parameters.

Experimental studies with ranolazine suggest that the most likely mechanism
of action is mediated through a partial reduction in fatty acid oxidation
and consequent reciprocal increase in glucose oxidation during periods of
myocardial stress, resulting in more adenosine triphosphate synthesized per
molecule of oxygen consumed.6- 9 To
confirm the proposed mechanism of action of ranolazine, in the clinical setting
of patients with angina, additional studies would need to be performed. Unlike
nitrates, β-blockers, and calcium antagonists that mediate their action
through hemodynamic effects, ranolazine did not have clinically significant
effects on heart rate or blood pressure, consistent with its proposed metabolic
mechanism.7,10 Ranolazine may
thus be well suited for patients with lower blood pressures or heart rates,
in whom the institution or upward titration of antianginal drugs with important
hemodynamic effects may not be tolerated.

The most common adverse effects with ranolazine were constipation, nausea,
asthenia, and dizziness, no more than 6.2% greater than what the placebo group
experienced for each reaction. Five patients taking 1000 mg of ranolazine
experienced syncope. Four of the 5 were taking diltiazem, which is known to
increase ranolazine plasma levels,25 and all
were taking an angiotensin-converting enzyme inhibitor. Although little or
no effect of ranolazine on mean blood pressures has been observed over the
dose range of 500 mg to 1000 mg twice daily, postural hypotension and syncope
have occurred in healthy volunteers given higher doses, up to 2000 mg twice
daily. This is likely due to α1-adrenergic receptor blocking
activity at higher doses and plasma concentrations. Thus, syncope should be
avoidable by the usual clinical practice of initiating antianginal therapy
with the lowest available dose and carefully titrating upward based on both
efficacy and tolerability. Small QTc increases (<10 milliseconds vs placebo,
on average) were not associated with persistent, frank QT prolongation in
any patient nor with a mean increase in QT dispersion. Torsade de pointes
has not been reported on ranolazine. The ECG effects with ranolazine appear
to be balanced between inhibition of the potassium currents, IKr and
IKs , which lengthens the QT, and inhibition of the late sodium
current, late INa,26 that suppresses
early after depolarizations in isolated cardiomyocytes.

One- and 2-year survival rates of 98.4% and 95.9% with ranolazine are
not worrisome, considering that these patients had severe chronic angina,
with about four angina attacks per week at baseline, and exercise-induced
angina and ischemic ST segment depression at workloads of less than 5 metabolic
equivalents. Annual mortality rates in such patients have been reported ranging
from 4% to 13%.27,28

In conclusion, ranolazine affords additional anti-anginal and anti-ischemic
efficacy in patients with severe chronic angina who remain symptomatic while
taking standard doses of atenolol, amlodipine, or diltiazem, with minimal
hemodynamic effects and without evident adverse long-term survival consequences
over 1 to 2 years of therapy. It may be particularly useful in patients who
cannot tolerate the initiation or upward titration of currently available
antianginal drugs because of their depressive effects on blood pressure and
heart rate.

US Department of Health and Human Services, National Center for Health
Statistics. Third National Health and Nutrition Examination Survey,
(NHANES III), 1988-1994 [CD-ROM], Hyattsville, Md: Centers for Disease
Control and Prevention; 1997. Series 11, No. 1, revised October 1997.

Figures

Figure 1. Patient Study Flow Diagram

Safety data are presented for all 823 patients who received at least
1 dose of study medication. Efficacy data are available from 791 patients
(737 patients completed the full 12-week protocol and 54 patients had the
last observation carried forward).

Figure 2. Change in Treadmill Exercise Duration
From Baseline at Trough Ranolazine Levels Over Time

US Department of Health and Human Services, National Center for Health
Statistics. Third National Health and Nutrition Examination Survey,
(NHANES III), 1988-1994 [CD-ROM], Hyattsville, Md: Centers for Disease
Control and Prevention; 1997. Series 11, No. 1, revised October 1997.

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